TY - JOUR
T1 - Optimized induction of mitochondrial apoptosis for chemotherapy-free treatment of BCR-ABL+acute lymphoblastic leukemia
AU - Scherr, Michaela
AU - Kirchhoff, Hanna
AU - Battmer, Karin
AU - Wohlan, Katharina
AU - Lee, Chun-Wei
AU - Ricke-Hoch, Melanie
AU - Erschow, Sergej
AU - Law, Edward
AU - Kloos, Arnold
AU - Heuser, Michael
AU - Ganser, Arnold
AU - Hilfiker-Kleiner, Denise
AU - Heidenreich, Olaf
AU - Eder, Matthias
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2019/6
Y1 - 2019/6
N2 - BCR-ABL+acute lymphoblastic leukemia (ALL) in adults has a poor prognosis with allogeneic stem cell transplantation (SCT) considered the best curative option for suitable patients. We here characterize the curative potential of BH3-mimetics differentially targeting mitochondrial BCL2-family members using a combination therapy approach with dexamethasone and tyrosine kinase inhibitors targeting BCR-ABL. In BCR-ABL + ALL BH3-mimetics act by redistribution of mitochondrial activator BIM, which is strongly required for cytotoxicity of the BCL2-specific BH3-mimetic ABT-199, tyrosine kinase inhibitors (TKIs) and dexamethasone. BIM expression is enhanced by dexamethasone and TKIs and both synergize with ABT-199 in BCR-ABL + ALL. Triple combinations with ABT-199, dexamethasone and TKIs efficiently attenuate leukemia progression both in tissue culture and in primary cell xenotransplantation models. Notably, the dasatinib-containing combination led to treatment- and leukemia-free long-term survival in a BCR-ABL + mouse model. Finally, response to BH3-mimetics can be predicted for individual patients in a clinically relevant setting. These data demonstrate curative targeted and chemotherapy-free pharmacotherapy for BCR-ABL + ALL in a preclinical model. Clinical evaluation, in particular for patients not suitable for allogeneic SCT, is warranted.
AB - BCR-ABL+acute lymphoblastic leukemia (ALL) in adults has a poor prognosis with allogeneic stem cell transplantation (SCT) considered the best curative option for suitable patients. We here characterize the curative potential of BH3-mimetics differentially targeting mitochondrial BCL2-family members using a combination therapy approach with dexamethasone and tyrosine kinase inhibitors targeting BCR-ABL. In BCR-ABL + ALL BH3-mimetics act by redistribution of mitochondrial activator BIM, which is strongly required for cytotoxicity of the BCL2-specific BH3-mimetic ABT-199, tyrosine kinase inhibitors (TKIs) and dexamethasone. BIM expression is enhanced by dexamethasone and TKIs and both synergize with ABT-199 in BCR-ABL + ALL. Triple combinations with ABT-199, dexamethasone and TKIs efficiently attenuate leukemia progression both in tissue culture and in primary cell xenotransplantation models. Notably, the dasatinib-containing combination led to treatment- and leukemia-free long-term survival in a BCR-ABL + mouse model. Finally, response to BH3-mimetics can be predicted for individual patients in a clinically relevant setting. These data demonstrate curative targeted and chemotherapy-free pharmacotherapy for BCR-ABL + ALL in a preclinical model. Clinical evaluation, in particular for patients not suitable for allogeneic SCT, is warranted.
KW - Animals
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Apoptosis/drug effects
KW - Bridged Bicyclo Compounds, Heterocyclic/administration & dosage
KW - Dasatinib/administration & dosage
KW - Dexamethasone/administration & dosage
KW - Drug Resistance, Neoplasm
KW - Humans
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
KW - Mice
KW - Mice, Inbred NOD
KW - Mice, SCID
KW - Mitochondria/drug effects
KW - Sulfonamides/administration & dosage
KW - Tumor Cells, Cultured
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=85058435487&partnerID=8YFLogxK
U2 - 10.1038/s41375-018-0315-6
DO - 10.1038/s41375-018-0315-6
M3 - Article
C2 - 30546081
SN - 0887-6924
VL - 33
SP - 1313
EP - 1323
JO - Leukemia
JF - Leukemia
IS - 6
ER -